PROJECT SUMMARY/ABSTRACT Depression in HIV is associated with worse HIV outcomes including worse engagement in care, medication adherence, and retention in care. Depression is also three times more prevalent in those with HIV than in the general population. While there are complex reasons including psychosocial, there is a growing body of evidence that inflammation is linked to mental illness including depression although the underlying pathophysiology in people living with HIV is not well understood. Better understanding of the pathogenesis will help identify new treatments. Better depression treatments may thereby lead to engagement/retention in care and better HIV outcomes including virologic control. Better HIV control will help achieve the UNAIDS 90/90/90 goals to diagnose 90% of all HIV-positive persons, provide ART for 90% of those diagnosed, and achieve viral suppression for 90% of those treated. The Specific Aims of this K23 award are: 1) To determine if CSF inflammation and neuronal damage are associated with depression in HIV-infected Ugandans and 2) Determine if the prevalence of depression at 26 weeks of HIV therapy is improved with group psychotherapy and antidepressant medicine over antidepressant medicine alone and determine if the persistence of depression is associated with higher levels of innate inflammation due to the systemic stress response. I hypothesize that depression is associated with dysregulated innate inflammatory signaling in CSF in HIV-infected persons. I also hypothesize that in HIV- infected Ugandans with CD4 <200 cells/?L and depression initiating HIV therapy, those with persisting depression at 26 weeks will have increased plasma interleukin-6 and cortisol compared to persons whose depression resolves. I further hypothesize that structured weekly group psychotherapy will reduce depressive symptoms, measured by patient health questionnaire-9 (PHQ-9) at 26 weeks of HIV therapy. Dr. Lofgren?s long-term career goal is to become an independent translational researcher who bridges the gap between mental health and immunology, moving basic science concepts to clinical application in resource- limited settings. During her training to date, Dr. Lofgren has spent three years performing clinical research in East Africa, and all of the last two years divided between Minnesota and Kampala, Uganda. This K23 award will provide for mentored career development using a combination of coursework to supplement current knowledge gaps and practical mentored-research experience to build a strong foundation of research skills in mental health, immunology and neuroscience. This will allow her to be an expert in psychoneuroimmunology. The award will build upon existing international collaborations allowing the candidate to apply her K23 training into clinical and translational research among persons living with depression and advanced HIV/AIDS with CD4<200 cells/?L.